The abuse of prescription narcotic drugs alone in the U.S. is presently an enormous and growing problem. In 2011, about 420,000 emergency room (ER) episodes (nearly 1150/day) resulted from the abuse of prescription opioids, an increase of 153% from 2004. ER episodes from oxycodone (Oxycontin) alone increased 220% during this period. &#8232;&#8232; These drugs exert their effects through the opioid receptor-endorphin system that consists of saturable, enantioselective, high affinity mu, delta and kappa opioid receptor types located in anatomically well defined areas of the mammalian CNS. Numerous endogenous opioid peptides (endorphins) function as the endogenous ligands for these receptors. This system mediates the analgesic, euphoric and addictive effects of narcotic drugs and contributes to regulation of numerous physiologic and behavioral functions in its normal state. Prescription opioids, heroin, and other narcotic drugs mimic some of the actions of the natural endorphins but dysregulate the system resulting in the development of narcotic tolerance and dependence among other undesired side effects. In our program to further understand the complex pharmacology of opioid drugs and develop strategies for treatment and prevention of their abuse and side effects we are pursuing several approaches. In one such approach, we are exploiting recent pharmacologic advances that (a) have shown that highly selective delta receptor antagonists might be valuable medications for the treatment and prevention of human narcotic abuse and (b) that a drug showing a mu agonist-delta antagonist profile might produce strong analgesia without producing tolerance and dependence thus allowing continuous treatment of chronic pain. Optimal exploitation of these and other similarly intriguing observations now requires novel, exquisitely selective, nonpeptide ligands as research tools and potential medications. These new tools will enable the study of many questions of fundamental importance concerning the function of mu, delta and kappa opioid receptor subtypes and how drugs interact with their receptors to elicit these functions. We have continued to design, synthesize and evaluate novel drugs for this purpose during the reporting period. We earlier identified a mu agonist-delta antagonist and a delta inverse agonist in the 5-phenylmorphan series, a particularly interesting class of opioid receptor agonists that were originated by Everette May at NIH in 1955. We recently identified a morphine-like mu agonist and also a mu antagonist in a series of conformationally restrained 5-phenylmorphans. The diverse profiles obtained in this series illustrate the importance of subtle changes on the carbon-nitrogen skeleton and careful attention to stereochemical detail and provide important leads toward novel pain medications with reduced side effects and further understanding of drug-receptor interactions. We recently described novel N-phenethyl substituted tricyclic N-substituted-2,3,4,9,10,10a-hexahydro-1H-1,4a-(epiminoethano)phenanthren-6- and 8-ols. Conceptionally, these compounds result when a two carbon-bridge replaces the dihydrofuran ring of the f-isomer oxide-bridged 5-phenylmorphans. This modification provides additional flexibility in the molecule and results in compounds with high mu antagonist activity comparable to naltrexone. Finally, we are employing collaborative computer assisted molecular modeling and ab initio quantum mechanical methods in the design of related compounds. Our studies are exploiting recent landmark biophysical advances that resulted in X-ray structural determination of the mu, delta and kappa opioid receptors. These are enormously important results that will enable a much more precise understanding of how different classes of opioid drugs interact with the receptors to elicit their effects, both desirable and undesirable. We are also pursuing the development of an anti-heroin vaccine for the treatment and prevention of heroin abuse. A successful vaccine of this type would suppress heroin abuse and the accompanying needle sharing and spread of HIV and hepatitis. We have completed the complex chemical synthesis of the required heroin mimetic haptens and prepared experimental vaccines and testing these vaccines is now in progress. We filed a provisional patent application with our collaborators at Walter Reed Army Institute of Research on induction of highly specific antibodies that was published as WO2013119954 in 2013.